Device for in vivo delivery of bioactive agents and method of manufacture thereof

ABSTRACT

The disclosure of the invention provides an implantable structural element for in vivo delivery of bioactive agents to a situs in a body. The implantable structural element may be configured as an implantable prosthesis, such as an endoluminal stent, cardiac valve, osteal implant or the like, which serves a dual function of being prosthetic and a carrier for a bioactive agent. Alternatively, the implantable structural element may simply be an implantable article that serves the single function of acting as a time-release carrier for the bioactive agent.

BACKGROUND OF THE INVENTION

The present invention relates generally to an implantable device for invivo delivery of bioactive compounds. The present invention provides animplantable structural material having a three-dimensional conformationsuitable for loading a bioactive agent into the structural material,implanting the structural material in vivo and releasing the bioactiveagent from the structural agent to deliver a pharmacologicallyacceptable level of the bioactive agent to an internal region of a body.More particularly, the present invention relates to an implantablemedical device, such as an endoluminal stent, stent-graft, graft,valves, filters, occluders, osteal implant or the like, having cavitatedregions with micropores that communicate a bioactive agent from thecavity to an area external the stent.

The present invention may be used for any indication where it isdesirable to deliver a bioactive agent to a local situs within a bodyover a period of time. For example, the present invention may be used intreating vascular occlusive disease, disorders or vascular injury, as animplantable contraceptive for delivery of a contraceptive agentdelivered intrauterine or subcutaneously, to carry an anti-neoplasticagent or radioactive agent and implanted within or adjacent to a tumor,such as to treat prostate cancer, for time-mediated delivery ofimmunosuppresents, antiviral or antibiotic agents for treating ofautoimmune disorders such as transplantation rejection or acquiredimmune disorders such as HIV, or to treat implant or non-implant-relatedinflammation or infections such as endocarditis.

Occlusive diseases, disorders or trauma cause patent body lumens tonarrow and restrict the flow or passage of fluid or materials throughthe body lumen. One example of occlusive disease is arteriosclerosis inwhich portions of blood vessels become occluded by the gradual build-upof arteriosclerotic plaque. This process is also known as stenosis. Whenvascular stenosis results in the functional occlusion of a blood vesselthe vessel must be returned to its patent condition. Conventionaltherapies for treatment of occluded body lumens include dilatation ofthe body lumen using bioactive agents, such as tissue plasminogenactivator (TPA) or vascular endothelial growth factor (VEGF) andfibroblast growth factor (FGF) gene transfers which have improved bloodflow and collateral development in ischemic limb and myocardium (S.Yla-Herttuala, Cardiovascular gene therapy, Lancet, Jan. 15, 2000),surgical intervention to remove the blockage, replacement of the blockedsegment with a new segment of endogenous or exogenous graft tissue, orthe use of a catheter-mounted device such as a balloon catheter todilate the body lumen or an artherectomy catheter to remove occlusivematerial. The dilation of a blood vessel with a balloon catheter iscalled percutaneous transluminal angioplasty. During angioplasty, aballoon catheter in a deflated state is inserted within an occludedsegment of a blood vessel and is inflated and deflated a number of timesto expand the vessel. Due to the inflation of the balloon catheter, theplaque formed on the vessel walls cracks and the vessel expands to allowincreased blood flow through the vessel.

In approximately sixty percent of angioplasty cases, the blood vesselremains patent. However, the restenosis rate of approximately fortypercent is unacceptably high. Endoluminal stents of a wide variety ofmaterials, properties and configurations have been used post-angioplastyin order to prevent restenosis and loss of patency in the vessel.

While the use of endoluminal stents has successfully decreased the rateof restenosis in angioplasty patients, it has been found that asignificant restenosis rate continues to exist even with the use ofendoluminal stents. It is generally believed that the post-stentingrestenosis rate is due, in major part, to a failure of the endotheliallayer to regrow over the stent and the incidence of smooth musclecell-related neointimal growth on the luminal surfaces of the stent.Injury to the endothelium, the natural nonthrombogenic lining of thearterial lumen, is a significant factor contributing to restenosis atthe situs of a stent. Endothelial loss exposes thrombogenic arterialwall proteins, which, along with the generally thrombogenic nature ofmany prosthetic materials, such as stainless steel, titanium, tantalum,Nitinol, etc. customarily used in manufacturing stents, initiatesplatelet deposition and activation of the coagulation cascade, whichresults in thrombus formation, ranging from partial covering of theluminal surface of the stent to an occlusive thrombus. Additionally,endothelial loss at the site of the stent has been implicated in thedevelopment of neointimal hyperplasia at the stent situs. Accordingly,rapid re-endothelialization of the arterial wall with concomitantendothelialization of the body fluid or blood contacting surfaces of theimplanted device is considered critical for maintaining vasculaturepatency and preventing low-flow thrombosis. To prevent restenosis andthrombosis in the area where angioplasty has been performed,anti-thrombosis agents and other biologically active agents can beemployed.

It has been found desirable to deliver bioactive agents to the areawhere a stent is placed concurrently with stent implantation. Manystents have been designed to deliver bioactive agents to the anatomicalregion of stent implantation. Some of these stents are biodegradablestents which are impregnated with bioactive agents. Examples ofbiodegradable impregnated stents are those found in U.S. Pat. Nos.5,500,013, 5,429,634, and 5,443,458. Other known bioactive agentdelivery stents include a stent disclosed in U.S. Pat. No. 5,342,348 inwhich a bioactive agent is impregnated into filaments which are woveninto or laminated onto a stent. U.S. Pat. No. 5,234,456 discloses ahydrophilic stent which can include a biologically active agent disposedwithin the hydrophilic material of the stent. Other bioactive agentdelivery stents are disclosed in U.S. Pat. Nos. 5,201,778, 5,282,823,5,383,927; 5,383,928, 5,423,885, 5,441,515, 5,443,496, 5,449,382,4,464,450, and European Patent Application No. 0 528 039. Other devicesfor endoluminal delivery of bioactive agents are disclosed in U.S. Pat.Nos. 3,797,485, 4,203,442, 4,309,776, 4,479,796, 5,002,661, 5,062,829,5,180,366, 5,295,962, 5,304,121, 5,421,826, and InternationalApplication No. WO 94/18906. A directional release bioactive agent stentis disclosed in U.S. Pat. No. 6,071,305 in which a stent is formed of ahelical member that has a groove in the abluminal surface of the helicalmember. A bioactive agent is loaded into the groove prior to endoluminaldelivery and the bioactive agent is therefore in direct apposition tothe tissue that the bioactive agent treats. Finally, InternationalApplication No. WO 00/18327 discloses a drug delivery stent in which atubular conduit is wound into a helical stent. The tubular conduit haseither a single continuous lumen or dual continuous lumens that extendthe entire length of the conduit. The tubular conduit has regions orsegments thereof that have pores to permit drug “seepage” from theconduit. One end of the tubular conduit is in fluid flow communicationwith a fluid delivery catheter, which introduces a fluid, such as adrug, into the continuous lumen and through the pores. Wherebiodegradable or non-biodegradable polymer-based or polymer-coatedstents have been used, the polymers cause an immune inflammatoryresponse once the drug is eluted out of the polymer. Where a polymer isemployed as the bioactive agent carrier, it is, therefore, desirable toisolate the polymer from body tissues in order to limit the immuneinflammatory response after the bioactive agent has eluted as can beaccomplished with the present invention.

SUMMARY OF THE INVENTION

As used herein the term “bioactive agent” is intended to include one ormore pharmacologically active compounds which may be in combination withpharmaceutically acceptable carriers and, optionally, additionalingredients such as antioxidants, stabilizing agents, permeationenhancers, and the like. Examples of bioactive agents which may be usedin the present invention include but are not limited to antiviral drugs,antibiotic drugs, steroids, fibronectin, anti-clotting drugs,anti-platelet function drugs, drugs which prevent smooth muscle cellgrowth on inner surface wall of vessel, heparin, heparin fragments,aspirin, coumadin, tissue plasminogen activator (TPA), urokinase,hirudin, streptokinase, antiproliferatives (methotrexate, cisplatin,fluorouracil, Adriamycin), antioxidants (ascorbic acid, beta carotene,vitamin E), antimetabolites, thromboxane inhibitors, non-steroidal andsteroidal anti-inflammatory drugs, immunosuppresents, such as rapomycin,beta and calcium channel blockers, genetic materials including DNA andRNA fragments, complete expression genes, antibodies, lymphokines,growth factors (vascular endothelial growth factor (VEGF) and fibroblastgrowth factor (FGF)), prostaglandins, leukotrienes, laminin, elastin,collagen, nitric oxide (NO) and integrins.

The inventive structural material has a three dimensional conformationhaving a geometry and construction in which there is an internal cavityor a plurality of internal cavities within the structural material and aconduit or opening or plurality of conduits or openings whichcommunicate between the internal cavity and external the structuralmaterial. The three dimensional conformation of the structural materialmay assume a cylindrical, tubular, planar, spherical, curvilinear orother general shape which is desired and suited for a particular implantapplication. For example, in accordance with the present invention thereis provided an endoluminal stent that is made of a plurality ofstructural members that define a generally tubular shape for theendoluminal stent. At least some of the plurality of structural membersare comprised of the inventive structural material and have at least oneinternal cavity and at least one conduit or opening which communicatesbetween the internal cavity and external the stent. Alternate types ofimplantable devices contemplated by the present invention include,without limitation, stent-grafts, grafts, heart valves, venous valves,filters, occlusion devices, catheters, osteal implants, implantablecontraceptives, implantable anti-tumor pellets or rods, or otherimplantable medical devices.

The inventive stent for delivery of bioactive agents consists generallyof a plurality of structural elements, at least some of which haveinternal cavities that retain the bioactive agents, and openings thatpass between the internal cavities and the surface of the structuralelements to communicate the bioactive agent from the internal cavity toexternal the stent. Other than described herein, the present inventiondoes not depend upon the particular geometry, material, materialproperties or configuration of the stent.

Because of their use as a structural scaffold and the requirement thatstents be delivered using transcatheter approaches, stents necessarilyare delivered in a reduced diametric state and are expanded or allowedto expand in vivo to an enlarged diametric state. Thus, all stents havecertain structural regions that are subject to higher stress and strainconditions than other structural regions of the stent. Thus, it may beadvantageous to position the internal cavities that retain the bioactiveagents in structural regions of the stent that are subjected torelatively lower stress and strain during endoluminal delivery anddeployment. Alternatively, where delivery of a bolus of a bioactiveagent is desired, internal cavities may be positioned in regions thatundergo large deformation during delivery and deployment thereby forcingthe bioactive agent out of the internal cavity under the positivepressure exerted by the deformation. Diffusion forces, then, eluteremaining bioactive agent present in either the region of largedeformation or the regions of lower stress and strain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an implantable member in accordance withthe present invention.

FIG. 2 is a perspective view of an endoluminal stent having a pluralityof structural member in accordance with the present invention.

FIG. 3 is a cross-sectional view taken along line 3-3 of FIG. 2.

FIG. 4 is a cross-sectional view taken along line 4-4 of FIG. 2.

FIG. 5 is a fragmentary perspective view of an alternative embodiment ofthe inventive endoluminal stent in accordance with the presentinvention.

FIG. 6 is a cross-sectional view taken along line 6-6 of FIG. 5.

FIG. 7 is a cross-sectional view taken along line 7-7 of FIG. 5.

FIG. 8 is a perspective view of a planar structural element for deliveryof a bioactive agent in accordance with the present invention.

FIG. 9 is a cross-sectional view taken along line 9-9 of FIG. 8.

FIG. 10 is a cross-sectional view taken along line 10-10 of FIG. 8.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As noted above, the term “bioactive agent” is intended to encompass oneor more pharmacologically active compounds which may be in combinationwith pharmaceutically acceptable carriers and, optionally, additionalingredients such as antioxidants, stabilizing agents, permeationenhancers, and the like. Examples of bioactive agents which may be usedin the present invention include but are not limited to antibioticdrugs, antiviral drugs, neoplastic agents, steroids, fibronectin,anti-clotting drugs, anti-platelet function drugs, drugs which preventsmooth muscle cell growth on inner surface wall of vessel, heparin,heparin fragments, aspirin, coumadin, tissue plasminogen activator(TPA), urokinase, hirudin, streptokinase, antiproliferatives(methotrexate, cisplatin, fluorouracil, Adriamycin), antioxidants(ascorbic acid, beta carotene, vitamin E), antimetabolites, thromboxaneinhibitors, non-steroidal and steroidal anti-inflammatory drugs,immunosuppresents, such as rapomycin, beta and calcium channel blockers,genetic materials including DNA and RNA fragments, complete expressiongenes, antibodies, lymphokines, growth factors (vascular endothelialgrowth factor (VEGF) and fibroblast growth factor (FGF)),prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide(NO), and integrins.

With particular reference to FIG. 1, the present invention consistsgenerally of a body element 10 having a three-dimensional conformationdefining X, Y and Z-axes of the body element 10 and at least one of aplurality of interior cavities 12 defined within the body element 10,and at least one of a plurality of passages or pores 14 whichcommunicate between the at least one of a plurality of interior cavities12 and exterior to the body element 10. While the body element 10depicted in FIG. 1 is of a generally cylindrical three dimensionalconformation, alternative three dimensional conformations, such asplanar, spherical, ovular, tetrahedral, curvilinear or virtually anyother three dimensional conformation suitable for implantation into aliving body are contemplated by the present invention. The plurality ofpassages 14 have dimensions sufficient to permit the bioactive agent toelute by diffusion, osmotic pressure or under the influence of apositive pressure applied by cellular in-growth into the plurality ofinterior cavities 12.

The location of the plurality of passages 14 is dependent upon theparticular application for which the body element 10 is intended. Forexample, with particular reference to FIGS. 2-4, where the body element10 is a tubular body 20 made of a plurality of interconnected structuralelements 21, such as a stent, stent-graft or graft, which defines acentral lumen 22 and has openings 24 at opposing proximal and distalends of the tubular body 20, the plurality of passages 14 are formed inat least some of the plurality of interconnected structural elements 21and may be disposed on only the luminal surface 26 or only on theabluminal surface 28 of the tubular body 20, or both. Pores 14 on theluminal surface 26 only will communicate the bioactive agent into thelumen 22 and any body fluid, such as blood, flowing through the centrallumen 22 of the tubular body 20, while pores 14 on only the abluminalsurface 28 will communicate the bioactive agent to the abluminal surface28 of the tubular body 20. At least a portion of some of the pluralityof interior cavities 12 may communicate with either the proximal ordistal ends of at least some of the plurality of interconnectedstructural elements 21. In this case, the proximal and/or distal ends ofat least some of the plurality of interconnected structural elements 21may be tapered such as to be self-cannulating into body tissue duringdelivery and deployment. The bioactive agent retained within theinternal cavity 12 which communicates with the proximal and/or distalends of at least some of the plurality of interconnected structuralelements 21 will then pass out of the proximal and/or distal ends inmuch the same manner as fluid flowing through an injection needle.

In addition to the foregoing positioning of the pores 14, both theplurality of internal cavities 12 and the plurality of pores 14 may bepositioned to be discontinuous and in different circumferential ordifferent longitudinal regions of the tubular body 20. Within a singleone of the plurality of interconnected structural elements 21, theinternal cavities 12 may be separated by a separation member 25, whichcompletely subtends the internal cavity 12, dividing it into discretediscontinuous internal cavities 12. The advantage of forming a pluralityof discontinuous internal cavities 12 is that it permits loading ofdifferent bioactive agents into different regions of the body member 10or tubular member 20 to isolate different regions for delivery ofdifferent bioactive agents to different sites within a body. Forexample, a first grouping of a plurality of internal cavities 12 andassociated plurality of pores 14 may be located at a proximal end of thetubular body 20, and a second grouping of a plurality of internalcavities 12 and associated plurality of pores 14 may be located at anintermediate region of the tubular body 20, and a third grouping of aplurality of internal cavities 12 and associated plurality of pores 14may be located at a distal end of the tubular body 20. A first bioactiveagent may be loaded into the first and third grouping of a plurality ofinternal cavities 12, while a second bioactive agent may be loaded intothe second grouping of a plurality of internal cavities 12. Where, forexample, the tubular body 20 is an endoluminal stent, stent-graft orgraft which is implanted post-angioplasty, the proximal and distal endsof the tubular body 20 are anchored adjacent to healthy tissue while theintermediate region of the tubular body 20 is positioned adjacent to thediseased or injured tissue. In this configuration, a first bioactiveagent, such as an endothelial growth factor and/or contrast medium toimpart enhanced radiopacity to the tubular body 20 may be carried in thefirst and third groups of a plurality of internal cavities 12 andassociated pores 14, while an anticoagulant, such as heparin, may becarried in the second grouping of a plurality of internal cavities 12and associated pores 14. In this manner, the tubular body has enhancedradiopacity to aid in delivery and deployment and endothelial growthfactors to enhance endothelialization of the tubular body 20, whiledelivering an anticoagulant directly to the site of the tissue lesion.

Moreover, where the internal cavities 12 are discontinuous, theplurality of pores 14 may be configured to include degradable plugswhich degrade at different rates to expose different bioactive agents inthe internal cavities 12 to the body at different points in time.Alternatively or additionally, the degradable plugs may degrade atdifferent rates to expose the same bioactive agent in different internalcavities 12 at different periods of time to effectively elongate theperiod of time during which the bioactive agent is delivered.

The body element 10 is preferably formed of a metal such as titanium,vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold,silicon, magnesium, niobium, scandium, platinum, cobalt, palladium,manganese, molybdenum and alloys thereof, such aszirconium-titanium-tantalum alloys, nitinol, or stainless steel.

Turning to FIGS. 5-7 there is illustrated an alternative embodiment ofthe inventive endoluminal stent 30 fabricated from a plurality oftubular structural elements 31 formed into a tubular stent and having adesired geometry. It will be appreciated that the generally hexagonalcell geometric pattern defining a plurality of interstices 32 asillustrated in FIG. 5 is merely exemplary and a myriad of differentgeometries of different geometric complexities are contemplated by theinvention. Each of the tubular structural elements 31 has a centrallumen that forms the internal cavity 37 within each structural element31. A plurality of separation members 38 may be provided to subdividethe internal cavity 37 into a plurality of discontinuous internalcavities 37. Each of the tubular structural elements 31 has a pluralityof openings 36 which communicate between the internal cavity 37 and oneor both of a luminal surface 33 or an abluminal surface 35 of each ofthe plurality of tubular structural elements 31. The tubular structuralelements 31 may assume any transverse cross-sectional configurationhaving a central lumen.

Those of ordinary skill in the stent forming arts will understand thatin order to form a tubular endoluminal stent 30 of tubular elements 31,it is necessary to join at least some of the plurality of tubularelements 31. Conventionally, a plurality of spot-welds 34 serve tointerconnect sections of individual tubular elements 31 in juxtaposedrelationship to one and other. The plurality of spot welds 34 may alsobe employed to seal the internal cavity 37 at the position of the spotweld, thereby creating a separation member 38 within the internal cavity37 of each individual tubular element 31 and forming discontinuousinternal cavities 37.

As noted above, the plurality of openings 36 are dimensioned to permitthe bioactive agent to elute from the at least one of a plurality ofinternal cavities 37 and through the associated plurality of openings 36by diffusion, osmotic pressure or under the influence of a positivepressure applied by cellular in-growth into the plurality of internalcavities 37 or under positive pressure applied by stress and/or strainexerted on the plurality of internal cavities 37 due to deformation ofthe individual tubular structural elements 31. Additionally, thepositioning of the plurality of openings 36 relative to the individualtubular structural elements 31 and to the endoluminal stent 30 as awhole may be adapted to deliver varying quantities of or differentbioactive agents from different regions of the tubular structuralelements 31 or different regions of the endoluminal stent 30. Moreover,proximal and/or distal ends of individual tubular structural elements 31may be tapered so as to form self-cannulating ends of the individualtubular structural elements 31 which penetrate body tissue and permitthe bioactive agent to be communicated from the internal cavity 37 outthe proximal or distal end of the tubular structural element 31 in amanner similar to a hypodermic needle.

In accordance with another embodiment of the present invention, and asillustrated in FIGS. 8-10, there is provided an implantable device 40which consists of a structural body 42 having a three-dimensionalconformation extending in the X-axis, Y-axis and Z-axis dimensions.While the illustrated embodiment of the structural body 42 is planar,those of ordinary skill in the medical device fabrication art willunderstand that it is within the skill of the artisan to fabricate thestructural body 42 of any desired three-dimensional conformationdepending upon the desired use and indication of the implantable device40. The three-dimensional conformation of the structural body 42 may becylindrical, tubular, quadrilinear, planar, spherical, ovular,tetrahedral, curvilinear or virtually any other three-dimensionalconformation suitable for implantation into a living body.

Like the above-described embodiments, the structural body 42 has atleast one of a plurality of internal cavities 47, each of which carry abioactive agent 49, and a plurality of openings 44 which pass from atleast one upper 46, lower 48 or lateral 45 surface of the structuralbody 42, through the Z-axis thickness of the body and communicate withthe at least one of a plurality of internal cavities 47 in thestructural body 42. Where a plurality of internal cavities 47 areprovided within the structural body 42, a plurality of bioactive agents49 may be loaded into the structural body 42 with one or more bioactiveagents 49 being loaded into each of the plurality of internal cavities47.

Each of the above-described preferred embodiments of the presentinvention may be fabricated by a number of methods. In accordance withpresent invention, it is contemplated that forming the implantabledevices by vacuum deposition techniques is the preferred method ofmaking the implantable structural elements of the present invention.Where an implantable device is to be fabricated of a plurality ofindividual tubular wire elements, such as depicted in FIGS. 5-7,pre-existing microtubular wire members having an outer diameter, forexample, between 60 and 400 μm and a wall thickness of between 10 and350 μm, may be employed to fabricate extremely small dimensioned devicessuitable for intracranial or coronary artery applications. The pluralityof openings passing through the wall of each of the individual tubularwire elements may be formed by microdrilling the openings through thewall and into the internal cavity or lumen of the individual tubularwire members. The plurality of openings may be laser cut, etched orformed by EDM methods, and may be formed either pre- or post-formationof the wire members into the three-dimensional conformation of theimplantable device. Where an implantable device is to be formed fromnon-preexisting structural elements, vacuum deposition techniques may beemployed to form the implantable structural body, such as sputtering,reactive ion etching, chemical vapor deposition, plasma vapordeposition, or the like, as are known in the microelectronicsfabrication arts and are more fully described in co-pending, commonlyassigned U.S. patent application Ser. No. 09/443,929, filed Nov. 19,1999, which is hereby incorporated by reference. Because, the internalcavities and openings must be formed during deposition, the vacuumdeposition techniques must be modified to deposit requisite patterns ofsacrificial material to form the regions of the internal cavities andopenings, over a base layer of structural material, then depositing asecond layer of structural material over the sacrificial material andthe base layer. The sacrificial material may then be removed, such as byetching, to leave the internal cavities and plurality of openings formedwithin the deposited bulk material.

Regardless of which fabrication method is employed, the bioactive agentmust be loaded into the internal cavities of the implantable device.Loading of the bioactive agent may be accomplished by flowing a liquidor semi-liquid state of the bioactive agent through the plurality ofopenings and into the internal cavities, either throughout the entiredevice or in regions of the implantable device. Flow loading may befacilitated by applying positive pressure, temperature change or both,such as is used in hot isostatic pressing (HIP). In HIP the pressurizingmedium is typically a gas, and the process is carried out at elevatedtemperatures for specific time periods. While HIP is typically utilizedto densify materials, to heal casting defects and voids, or to bondsimilar or dissimilar materials it may be used to drive a fluid orsemi-fluid from external the implantable device into the internalcavities of the implantable device. Alternatively, diffusion-mediatedloading, osmotic loading or vacuum loading may be employed to load thebioactive agent into the internal cavities.

While the present invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art willunderstand and appreciate that variations in structural materials,bioactive agents, fabrication methods, device configuration or deviceindication and use may be made without departing from the invention,which is limited in scope only by the claims appended hereto.

1. An endoluminal stent for delivering a bioactive agent to a situs in abody, comprising: a plurality of vacuum deposited structural elementsforming a radially expandable cylindrical member, the plurality ofvacuum deposited structural elements including a complex finishedgeometry, each of the plurality of vacuum deposited structural elementshaving a wall thickness; wherein the vacuum deposited structuralelements are fabricated of a metal and comprise a base layer and asecond layer covering the base layer, further comprising a void spaceintermediate the base and second layers that is enclosed therebetween; aplurality of pores passing through the second layer and communicatingwith the void space such that the void space is open only through theplurality of pores; and at least one bioactive agent retained within thevoid space and elutable through the plurality of pores.
 2. Theendoluminal stent according to claim 1, further comprising a degradableplug residing within the plurality of pores to prohibit release of theat least one bioactive agent until the degradation of the degradableplug.
 3. The endoluminal stent according to claim 1, wherein the metalis selected from the group consisting of titanium, vanadium, aluminum,nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium,niobium, scandium, platinum, cobalt, palladium, manganese, molybdenumand alloys thereof, including zirconium-titanium-tantalum alloys,nitinol, and stainless steel.
 4. The endoluminal stent according toclaim 1, wherein the bioactive agent further comprises apharmacologically active agent selected from the group consisting ofantibiotic drugs, antiviral drugs, neoplastic agents, steroids,fibronectin, anti-clotting drugs, anti-platelet function drugs, drugswhich prevent smooth muscle cell growth on inner surface wall of vessel,heparin, heparin fragments, aspirin, coumadin, tissue plasminogenactivator, urokinase, hirudin, streptokinase, antiproliferatives,methotrexate, cisplatin, fluorouracil, adriamycin, antioxidants,ascorbic acid, beta carotene, vitamin E, antimetabolites, thromboxaneinhibitors, non-steroidal and steroidal anti-inflammatory drugs,immunosuppresents, such as rapomycin, beta and calcium channel blockers,genetic materials including DNA and RNA fragments, complete expressiongenes, antibodies, lymphokines, growth factors, vascular endothelialgrowth factor and fibroblast growth factor, prostaglandins,leukotrienes, laminin, elastin, collagen, nitric oxide, and integrins.5. The endoluminal stent according to claim 1, wherein the void spacecomprises a plurality of independent internal cavities along the lengthof the structural elements.
 6. The endoluminal stent according to claim1, wherein the metal of the first and second layers has at least onesurface thereof having controlled heterogeneities thereupon.
 7. Theendoluminal stent according to claim 6, wherein the controlledheterogeneities are selected from the group consisting of grain size,grain phase, grain material composition and surface topography.
 8. Theendoluminal stent according to claim 6, wherein the controlledheterogeneities define polar and non-polar binding sites for bindingblood plasma proteins.
 9. The endoluminal stent according to claim 6,wherein the controlled heterogeneities are dimensioned to have a bloodcontact surface area substantially similar in size to endothelial cellsurface integrin clusters.
 10. The endoluminal stent according to claim6, wherein the controlled heterogeneities define cell-adhesion domainshaving interdomain boundaries less than the surface area of a humanendothelial cell.
 11. The endoluminal stent according to claim 6,wherein the controlled heterogeneities form binding domains having arepeating pattern with no more than about 2 μm border to border spacingbetween adjacent binding domains.
 12. The endoluminal stent according toclaim 6, wherein the controlled heterogeneities are dimensioned to havea blood contact surface area of about less than 6 μm².
 13. Theendoluminal stent according to claim 6, wherein the controlledheterogeneities have a blood contact surface less than or equal to about10 μm and an inter-heterogeneity boundary between about 0 and 2 μm.